The University of Southampton
University of Southampton Institutional Repository

Comparative efficacy and tolerability of medications for attention-deficit/hyperactivity disorder in children, adolescents and adults: a systematic review and network meta-analysis

Comparative efficacy and tolerability of medications for attention-deficit/hyperactivity disorder in children, adolescents and adults: a systematic review and network meta-analysis
Comparative efficacy and tolerability of medications for attention-deficit/hyperactivity disorder in children, adolescents and adults: a systematic review and network meta-analysis
Background
The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults.

Methods
We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976.

Findings
133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD −1·02, 95% CI −1·19 to −0·85 for amphetamines, −0·78, −0·93 to −0·62 for methylphenidate, −0·56, −0·66 to −0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD −0·82, 95% CI −1·16 to −0·48) and modafinil (−0·76, −1·15 to −0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD −0·79, 95% CI −0·99 to −0·58), methylphenidate (−0·49, −0·64 to −0·35), bupropion (−0·46, −0·85 to −0·07), and atomoxetine (−0·45, −0·58 to −0·32), but not modafinil (0·16, −0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36–3·89) and adults (3·26, 1·54–6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20–5·81); and atomoxetine (2·33, 1·28–4·25), methylphenidate (2·39, 1·40–4·08), and modafinil (4·01, 1·42–11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs −0·46 to −0·24) and adults (−0·94 to −0·29). We did not find sufficient data for the 26-week and 52-week timepoints.

Interpretation
Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs.

Funding
Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.
2215-0366
727-738
Cortese, Samuele
53d4bf2c-4e0e-4c77-9385-218350560fdb
Adamo, Nicoletta
9732c74f-8f27-429c-8031-155fe9cbdc9d
Del Giovane, Cinzia
4800e7ef-0abe-42e8-9358-d6285af9c5ec
Mohr-Jensen, Christina
f68a967b-7adf-49ce-b349-76649747e01f
Hayes, Adrian
70ee0f13-e84a-4cff-8bd7-4ac21b0493e9
Carucci, Sara
2b702c80-9cf2-4065-9d65-3340783be0d4
Atkinson, Lauren
8bfaa359-b3a3-4b63-9b05-da2e6ca0de1b
Tessari, Luca
2a879481-c19e-4fc9-8af0-474970992083
Banaschewski, Tobias
dc74faa9-30e1-4053-8fc6-aaac303d7cd4
Coghill, David
deea8957-fdfc-488a-a3bb-fb9b536c7172
Hollis, Chris
fe8adc7a-cfcd-4966-b397-1dd22048bbc8
Simonoff, Emily
f47d91a8-3d57-4183-bf24-80352c55eedc
Zuddas, Alessandro
51df7133-8494-4309-902d-bbf088341e46
Barbui, Corrado
dccf16d5-76c8-438a-9043-549e52dbde87
Purgato, Marianna
a72f5695-4d51-4247-a95f-b701df4cc04a
Steinhausen, Hans
972977d3-f9d2-425f-b7aa-4309707884d2
Shokraneh, Farhhad
84a14900-d109-46a0-99ae-c3927c62d332
Xia, Jun
67f140b7-d4b5-4dae-b84b-0351605aed4d
Cipriani, Andrea
5f3097c8-4901-4a9b-b371-d17aeac9b686
Cortese, Samuele
53d4bf2c-4e0e-4c77-9385-218350560fdb
Adamo, Nicoletta
9732c74f-8f27-429c-8031-155fe9cbdc9d
Del Giovane, Cinzia
4800e7ef-0abe-42e8-9358-d6285af9c5ec
Mohr-Jensen, Christina
f68a967b-7adf-49ce-b349-76649747e01f
Hayes, Adrian
70ee0f13-e84a-4cff-8bd7-4ac21b0493e9
Carucci, Sara
2b702c80-9cf2-4065-9d65-3340783be0d4
Atkinson, Lauren
8bfaa359-b3a3-4b63-9b05-da2e6ca0de1b
Tessari, Luca
2a879481-c19e-4fc9-8af0-474970992083
Banaschewski, Tobias
dc74faa9-30e1-4053-8fc6-aaac303d7cd4
Coghill, David
deea8957-fdfc-488a-a3bb-fb9b536c7172
Hollis, Chris
fe8adc7a-cfcd-4966-b397-1dd22048bbc8
Simonoff, Emily
f47d91a8-3d57-4183-bf24-80352c55eedc
Zuddas, Alessandro
51df7133-8494-4309-902d-bbf088341e46
Barbui, Corrado
dccf16d5-76c8-438a-9043-549e52dbde87
Purgato, Marianna
a72f5695-4d51-4247-a95f-b701df4cc04a
Steinhausen, Hans
972977d3-f9d2-425f-b7aa-4309707884d2
Shokraneh, Farhhad
84a14900-d109-46a0-99ae-c3927c62d332
Xia, Jun
67f140b7-d4b5-4dae-b84b-0351605aed4d
Cipriani, Andrea
5f3097c8-4901-4a9b-b371-d17aeac9b686

Cortese, Samuele, Adamo, Nicoletta, Del Giovane, Cinzia, Mohr-Jensen, Christina, Hayes, Adrian, Carucci, Sara, Atkinson, Lauren, Tessari, Luca, Banaschewski, Tobias, Coghill, David, Hollis, Chris, Simonoff, Emily, Zuddas, Alessandro, Barbui, Corrado, Purgato, Marianna, Steinhausen, Hans, Shokraneh, Farhhad, Xia, Jun and Cipriani, Andrea (2018) Comparative efficacy and tolerability of medications for attention-deficit/hyperactivity disorder in children, adolescents and adults: a systematic review and network meta-analysis. Lancet Psychiatry, 5 (9), 727-738. (doi:10.1016/S2215-0366(18)30269-4).

Record type: Article

Abstract

Background
The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults.

Methods
We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976.

Findings
133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD −1·02, 95% CI −1·19 to −0·85 for amphetamines, −0·78, −0·93 to −0·62 for methylphenidate, −0·56, −0·66 to −0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD −0·82, 95% CI −1·16 to −0·48) and modafinil (−0·76, −1·15 to −0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD −0·79, 95% CI −0·99 to −0·58), methylphenidate (−0·49, −0·64 to −0·35), bupropion (−0·46, −0·85 to −0·07), and atomoxetine (−0·45, −0·58 to −0·32), but not modafinil (0·16, −0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36–3·89) and adults (3·26, 1·54–6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20–5·81); and atomoxetine (2·33, 1·28–4·25), methylphenidate (2·39, 1·40–4·08), and modafinil (4·01, 1·42–11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs −0·46 to −0·24) and adults (−0·94 to −0·29). We did not find sufficient data for the 26-week and 52-week timepoints.

Interpretation
Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs.

Funding
Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Text
Cortese et al ADHD NMA REVISION Manuscript clean - Accepted Manuscript
Available under License Creative Commons Attribution.
Download (149kB)

More information

Accepted/In Press date: 5 July 2018
e-pub ahead of print date: 7 August 2018
Published date: September 2018

Identifiers

Local EPrints ID: 422395
URI: http://eprints.soton.ac.uk/id/eprint/422395
ISSN: 2215-0366
PURE UUID: b700eade-4e66-4a8d-8a14-466defde467b
ORCID for Samuele Cortese: ORCID iD orcid.org/0000-0001-5877-8075

Catalogue record

Date deposited: 23 Jul 2018 16:30
Last modified: 16 Mar 2024 06:52

Export record

Altmetrics

Contributors

Author: Samuele Cortese ORCID iD
Author: Nicoletta Adamo
Author: Cinzia Del Giovane
Author: Christina Mohr-Jensen
Author: Adrian Hayes
Author: Sara Carucci
Author: Lauren Atkinson
Author: Luca Tessari
Author: Tobias Banaschewski
Author: David Coghill
Author: Chris Hollis
Author: Emily Simonoff
Author: Alessandro Zuddas
Author: Corrado Barbui
Author: Marianna Purgato
Author: Hans Steinhausen
Author: Farhhad Shokraneh
Author: Jun Xia
Author: Andrea Cipriani

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×